Development of polysaccharide nanoparticles for the nasal administration of drugs for the treatment of neurodegenerative diseases

Abstract

The nasal delivery has been indicated as one of the most interesting alternative routes for brain delivery of drugs, since it is able to bypass the crossing of the blood brain barrier. The use of nanoparticles constitutes a promising approach for the transport of therapeutics across the nasal epithelium. However, the delivery of therapeutically relevant amounts of drugs exploiting the nasal route is strongly dependent on the permeation enhancement provided by those drug carriers. Along with their cholesterol lowering effect, statins have shown a wide range of pleiotropic effects potentially beneficial to neurodegenerative diseases, but extremely elusive via the conventional oral administration. The purpose of the present research work was to prepare and characterize the physico-chemical properties along the in vivo biodistribution and the in vitro efficacy of simvastatin-loaded nanoparticles, suitable for nasal administration in view of an improved delivery of statins to the brain. Chitosan, lecithin and different oil excipients were used to prepare nanocapsules loaded with simvastatin. Nanoparticles size distribution, surface charge, structure, encapsulation efficiency, drug release, nanoparticles interaction with mucus and drug transport across nasal epithelium models were determined. The nanoparticle toxicity was evaluated in vitro using nasal RPMI 2650 and human astrocytes cell lines. In vivo biodistribution was assessed by gamma scintigraphy via Tc99m labelling of the particles. Anti-apoptosis and anti-inflammatory properties of nanoparticles loading simvastatin were evaluated against an in vitro model of psychosine-induced astrocytes cellular toxicity. Finally, nanoparticles prevention of cerebellar demyelination was performed using the organotypic cerebellar slices culture excised from the brain of 10 days old mice. Simvastatin-loaded hybrid lecithin/chitosan nanoparticles developed present some of the most desiderated characteristics for mucosal delivery, i.e. small particle size, positive surface charge, long term stability, high encapsulation efficiency, mucoadhesion and permeation enhancing. However, they most exciting structural features are, firstly, their biodegradability by enzymes present in the mucus layer, such as lysozyme and phospholipase A2. This indicates a new trojan-horse strategy to enhance drug release in proximity of the nasal mucosa. Secondly, their ability to enhance the nose-to-brain transport as evidenced by preliminary gamma-scintigraphy studies. Lastly, loaded-nanoparticles regulation of pro-inflammatory cytokines release, prevention of psychosine-induced cellular death on astrocytes cells and the inhibition of demyelination on cerebellar mice slices, which suggest that hybrid nanoparticles technology may be useful in a range of demyelinating diseases, such Multiple Sclerosis, Alzheimer’s and Krabbe’s diseases. Concluding, hybrid lecithin/chitosan nanoparticles represent a novel, safe and promising strategy to guarantee drugs access to the cerebral parenchyma, exploiting an easy and non-invasive administering route, aiming an innovative treatment for several neurodegenerative disorders.